Rui He1, Dandan Zhang1, Wei Lu1, Taishan Zheng1, Lili Wan2, Fang Liu3, Weiping Jia4. 1. Department of Endocrinology and Metabolism, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai Clinical Medical Center of Diabetes, Shanghai Key Clinical Center of Metabolic Diseases, Shanghai Institute for Diabetes, Shanghai Key Laboratory of Diabetes, Shanghai 200233, China. 2. Department of Pharmacy, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, China. 3. Department of Endocrinology and Metabolism, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai Clinical Medical Center of Diabetes, Shanghai Key Clinical Center of Metabolic Diseases, Shanghai Institute for Diabetes, Shanghai Key Laboratory of Diabetes, Shanghai 200233, China. Electronic address: f-liu@sjtu.edu.cn. 4. Department of Endocrinology and Metabolism, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai Clinical Medical Center of Diabetes, Shanghai Key Clinical Center of Metabolic Diseases, Shanghai Institute for Diabetes, Shanghai Key Laboratory of Diabetes, Shanghai 200233, China. Electronic address: wpjia@sjtu.edu.cn.
Abstract
AIMS: The SLC47A1 gene encodes the multi-drug and toxic excretion-1(MATE1) protein, which plays a key role in the transport and excretion of metformin. This study is to clarify the influence of variants in SLC47A1 (rs2289669 G→A) on metformin pharmacokinetics and the long-term glucose-lowering effect of metformin. METHODS: A total of 220 newly diagnosed type 2 diabetes patients were recruited, genotyped and divided into three groups by SLC47A1 genotypes (G/G, G/A, A/A). Ten patients in each group were randomly selected for metformin pharmacokinetics. All the participants received metformin oral treatment and were followed for one year. RESULTS: After one-year follow-up, the decline of HbA1c level was significantly greater in subjects with variant genotype (AA) than other two groups (-2.32% [-25.4 mmol/mol] in AA vs. -1.16% [-12.7 mmol/mol] in GA, -1.07% [-11.7 mmol/mol] in GG, P<0.05). Then taking GG genotype as the referent, the association between AA genotype and change of HbA1c still existed after adjusted for age, sex, BMI, baseline HbA1c and diabetes duration (P<0.05). Pharmacokinetic parameters of metformin indicated that patients carrying MATE1 homozygous A had higher area under the plasma concentration versus time curve (AUC12h), but lower renal clearance (CLR) and renal clearance by secretion (CLSR) than other patients (all P<0.01). Multivariate lineal stepwise analysis further revealed that SLC47A1 genotype was an independent impact factor for urine excretion of metformin (P<0.01). CONCLUSIONS:SLC47A1rs2289669 G>A variants improve the glucose-lowering effect of metformin through slowing its excretion in type 2 diabetes populations.
RCT Entities:
AIMS: The SLC47A1 gene encodes the multi-drug and toxic excretion-1(MATE1) protein, which plays a key role in the transport and excretion of metformin. This study is to clarify the influence of variants in SLC47A1 (rs2289669 G→A) on metformin pharmacokinetics and the long-term glucose-lowering effect of metformin. METHODS: A total of 220 newly diagnosed type 2 diabetespatients were recruited, genotyped and divided into three groups by SLC47A1 genotypes (G/G, G/A, A/A). Ten patients in each group were randomly selected for metformin pharmacokinetics. All the participants received metformin oral treatment and were followed for one year. RESULTS: After one-year follow-up, the decline of HbA1c level was significantly greater in subjects with variant genotype (AA) than other two groups (-2.32% [-25.4 mmol/mol] in AA vs. -1.16% [-12.7 mmol/mol] in GA, -1.07% [-11.7 mmol/mol] in GG, P<0.05). Then taking GG genotype as the referent, the association between AA genotype and change of HbA1c still existed after adjusted for age, sex, BMI, baseline HbA1c and diabetes duration (P<0.05). Pharmacokinetic parameters of metformin indicated that patients carrying MATE1 homozygous A had higher area under the plasma concentration versus time curve (AUC12h), but lower renal clearance (CLR) and renal clearance by secretion (CLSR) than other patients (all P<0.01). Multivariate lineal stepwise analysis further revealed that SLC47A1 genotype was an independent impact factor for urine excretion of metformin (P<0.01). CONCLUSIONS:SLC47A1rs2289669 G>A variants improve the glucose-lowering effect of metformin through slowing its excretion in type 2 diabetes populations.
Authors: M A Daniels; C Kan; D M Willmes; K Ismail; F Pistrosch; D Hopkins; G Mingrone; S R Bornstein; A L Birkenfeld Journal: Pharmacogenomics J Date: 2016-07-19 Impact factor: 3.550